Achieving Long Timescale Sampling in Biomolecular Simulations

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This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).The objective of this research is to develop and apply efficient simulation methods to quantitatively describe complex biomolecular phenomena that usually occur in longer timescale than what conventional methods can achieve. Molecular recognition such as protein-ligand recognition and large conformational transition are two key elements in biomolecular machines. Due to timescale limitation, quantitative understanding of these events via computer simulation has been very challenging. In this project, efficient generalized ensemble simulation methods will be developed and employed to enhance the sampling power of biomolecular simulations. The promise of this project is particularly ensured by a recent methodological development in the PI's lab: the orthogonal space random walk (OSRW) algorithm, which can uniquely realize collective environmental relaxation in a robust and efficient manner. Specifically, three aims will be targeted: (1) understanding protein-protein interactions and protein electrostatics via OSRW based free energy simulations; (2) developing a hybrid quantum mechanical/molecular mechanical (QM/MM) based OSRW sampling scheme to more accurately describe protein-ligand interactions; (3) developing OSRW based conformational sampling methods to predict protein functional dynamics. In recent years, the PI has made tremendous efforts in organizing workshops and meetings to connect computational biophysics and experimental biophysics and to bridge method developments and biological applications. Some of these workshops, for instance, Telluride workshop on sampling enhancement, have become standing ones. In particular, the PI has been putting enormous emphasis in building multi-layered environments for young scientists so that they can receive suitable education to carry out multi-disciplinary research. In order for the advanced methods that are recently developed in the groups of PI and others to be quickly absorbed by the scientific community, the PI edited a special issue on free energy simulation in Journal of Computational Chemistry in early 2009 and is co-writing a book that is focused on modern simulation methods and their hand-on application. In addition, the developed methods through this project will be released in the program CHARMM, which can be widely employed by general scientific community.